DOCSLIB.ORG

In Vitro Antibacterial Activity Against Staphylococcus Aureus, Propionibacterium Acnes and Pseudomonas Aeruginosa

Total Page：16

File Type：pdf, Size：1020Kb

Download full-text PDF Read full-text
In Vitro Antibacterial Activity Against Staphylococcus Aureus, Propionibacterium Acnes and Pseudomonas Aeruginosa FULL PAPER Rational design and synthesis of modified teixobactin analogues: in vitro antibacterial activity against Staphylococcus aureus, Propionibacterium acnes and Pseudomonas aeruginosa [a] [b] *[a] Vivian Ng, Sarah A. Kuehne and Weng C. Chan Abstract: Teixobactin, a recently discovered depsipeptide that binds demonstrated excellent bactericidal activity against methicillin- to bacterial lipid II and lipid III, provides a promising molecular resistant Staphylococcus aureus (MRSA) which is associated scaffold for the design of new antimicrobials. Herein, we describe the with a wide range of infections in both the community (e.g. synthesis and antimicrobial evaluation of systematically modified cellulitis, abscesses) and the hospital settings (e.g. bacteraemia, teixobactin analogues. The replacement of Ile11 residue with aliphatic pneumonia).[4–6] Vancomycin is currently the last line of defence isosteres, the modification of the guanidino group at residue 10 and against MRSA infections but strains with reduced susceptibility the introduction of a rigidifying residue, dehydroamino acid into the to this antibiotic have surfaced.[7–10] Teixobactin offers a potential macrocyclic ring generated useful structure-activity information. solution to this predicament since it remains effective against Extensive antimicrobial susceptibility assessment against a panel of MRSA, as well as vancomycin-intermediate S. aureus (VISA) clinically relevant Staphylococcus aureus and Propionibacterium due to its unique mode of action.[4] It has been shown to acnes led to the identification of a new lead compound, synergistically block the biosyntheses of peptidoglycan and [Arg(Me)10,Nle11]teixobactin 63, with excellent bactericidal activity teichoic acid, thereby resulting in a weakened cell wall and (MIC 2–4 μg/mL). Significantly, the antimicrobial activity of several of autolysin-mediated cell lysis.[4,11] the teixobactin analogues against the pathogenic Gram-negative Teixobactin 1 is also a potent antimicrobial against another Pseudomonas aeruginosa was ‘restored’ when combined with sub- human skin commensal, Propionibacterium acnes.[4] This Gram- MIC concentration of the outer membrane-disruptive antibiotic, positive anaerobe is commonly associated with acnes colistin. The antimicrobial effectiveness of [Tfn10,Nle11]teixobactin 66 vulgaris.[12] In recent years, however, it is increasingly (32 μg/mL)-colistin (2 μg/mL; 0.5x MIC) combination against P. recognised as an opportunistic pathogen that can cause aeruginosa PAO1 reveals, for the first time, an alternative invasive infections, especially those associated with medical therapeutic option in the treatment of Gram-negative infections. implants.[13,14] There have been several reports on the isolation of P. acnes from prosthetic joints, cardiovascular devices and ophthalmic implants.[14–18] To aggravate matters, the widespread use of antibiotics to treat acne vulgaris has led to the emergence Introduction of P. acnes strains that are resistant to numerous antibiotics, including the macrolides, tetracycline and metronidazole.[13,19–22] Life-saving antibiotics are rapidly losing the race against the The need for novel antimicrobials is therefore more pressing development of bacterial resistance to most, if not all, antibiotics. than ever. It is hoped that teixobactin and its analogues may The resultant health and financial implications have spurred the serve as a timely solution to this clinically important pathogen. deployment of antimicrobial stewardship programmes across the globe to ensure evidence-based prescribing of antibiotics that are still effective.[1–3] Meanwhile, scientists are working hand-in- hand to tackle the resistance crisis through drug discovery and development initiatives. Natural antimicrobial peptides serve as invaluable molecular scaffolds for the development of the next generation of antimicrobial therapeutics. The recently discovered depsipeptide, teixobactin 1 (Figure 1), has great potential as a lead compound due to its favourable potency against many Structure of teixobactin and the four sites (blue) of modification Gram-positive pathogens.[4] Among them, teixobactin has Figure 1. 1 presented in this work. Teixobactin 1, comprised of a 13-membered depsipeptide [a] V. Ng, Dr W.C. Chan core and a tethered linear heptapeptide, offers multiple sites for School of Pharmacy, Centre for Biomolecular Sciences, synthetic modifications to improve its potency and efficacy. In University of Nottingham, University Park, Nottingham, U.K., NG7 2RD. less than three years since its discovery, more than a hundred E-mail: [email protected] analogues have been synthesized by various research groups in [b] Dr. S.A. Kuehne the hope of elucidating its structure-activity relationships School of Dentistry, and Institute for Microbiology and Infection, (SARs).[23–37] The biological activities of these analogues and the University of Birmingham, Birmingham, U.K., B5 7EG. different synthetic strategies reported have been comprehensively reviewed.[38,39] X-ray crystallographic, Supporting information for this article is given via a link at the end of molecular dynamic and NMR structural studies have also been the document. conducted to construct possible binding models of the native FULL PAPER peptide and its analogues.[26,27,40] Additionally, in a recent mini- review, we provided an insight into the structural similarities of teixobactin with other lipid II inhibitors.[41] Together, these resources provide tremendous information that could aid the design of optimised analogues. Early synthetic endeavours focused primarily on the exocyclic tail and the backbone stereochemistry of the native peptide. The replacement of any D-amino acid residues with its L-counterparts abolished activity, suggesting a significant contribution of these residues for the optimal conformation of teixobactin.[25,26,30] Yang et al. further demonstrated the importance of the N-terminal tail as the removal of the first five residues detrimentally affected antimicrobial potency.[24] Teixobactin appears to bind to the pyrophosphate and N- acetylmuramic acid amino sugar of lipid II. As such, its cyclic ring is believed to act as the main site of recognition.[4] With these considerations in mind, we have developed a series of analogues with modifications mainly on the macrocyclic core to Scheme 1. An optimized synthesis of Ni(II)-Gly-(S)-2-[N-(N- examine the significance of hydrophobicity at position 11, the benzylprolyl)amino]-benzophenone (BPB). cationic feature of the guanidino group at position 10, and the effect of introducing conformational rigidity at position 9. The N- Thus, using the protocol developed by Belokon et al., the Me-D-Phe1 was also replaced with D-Trp in an attempt to first step in the synthesis progressed smoothly to give N- investigate the contribution of the phenyl group. benzylated L-proline (S)-(3) in high yield.[43] Although the Apart from replacing the Ile residue at position 11 with condensation between (S)-(3) and 2-aminobenzophenone did readily available aliphatic isosteres, we sought to investigate the not proceed to completion, a reasonable yield of 45–60 % was effect of introducing fluorine atoms and unsaturated side-chain obtained. To our dismay, the use of KOH in the final step, i.e. at this position. Thus, Fmoc-(S)-6,6,6-trifluoronorleucine-OH the transformation of (S)-4 to (S)-5, gave a disappointing 50 % (Fmoc-Tfn-OH) and Fmoc-(S)-homoallylglycine-OH (Fmoc-Hag- recovery of (S)-5 after three recrystallizations. A review of the OH) were synthesized and their preparation will be discussed literature indicated that K2CO3 was previously employed by prior to the synthesis of the teixobactin analogues. All analogues Soloshonok and co-workers to prepare a closely related Schiff were extensively evaluated for their antimicrobial activity against base,[44] thereby suggesting that this alternative base could be both S. aureus and P. acnes. Thus far, most biological more effective for synthesizing (S)-5. Gratifyingly, K2CO3 (20 assessments of reported teixobactin analogues are focused on equiv.) drove the final reaction step to completion within an hour S. aureus and only the activity of the native peptide is known and (S)-5 was recrystallized from MeOH/H2O in >85 % yield. against P. acnes. Herein, we report detailed antimicrobial activity of teixobactin analogues against several P. acnes strains. Although teixobactin and analogues thereof are considered inactive against Gram-negative bacteria (MIC >256 μg/mL), the effect of using teixobactin analogues in combination with colistin was also investigated against the Gram-negative pathogen Pseudomonas aeruginosa. Results and Discussion Synthesis of Fmoc-(S)-6,6,6-trifluoronorleucine-OH and Fmoc-(S)-homoallylglycine-OH An operationally simple and cost-effective approach for the Scheme 2. An optimised synthesis of Fmoc-6,6,6-trifluoronorleucine-OH. asymmetric synthesis of Fmoc-Tfn-OH (S)-7 and Fmoc-Hag-OH (S)-9 is by alkylation of an achiral auxiliary reagent Ni(II)-glycine Having successfully prepared the Ni(II)-Schiff base (S)-5, Schiff base (S)-5.[42,43] The Ni(II)-complex (S)-5 was synthesized we then sought to optimise the alkylation of the complex with in large scale in three straightforward steps (Scheme 1). The 1,1,1-trifluoro-4-iodobutane (Scheme 2). Wang et al. have coordination of Ni(II) ion to the glycine greatly increased the previously reported a high diastereoselectivity (97%) was [45] acidity of the α-proton, enabling
Load more

Recommended publications
  • Dehydropeptide Supramolecular Hydrogels and Nanostructures As Potential Peptidomimetic Biomedical Materials
    International Journal of Molecular Sciences Review Dehydropeptide Supramolecular Hydrogels and Nanostructures as Potential Peptidomimetic Biomedical Materials Peter J. Jervis * , Carolina Amorim, Teresa Pereira, José A. Martins and Paula M. T. Ferreira Centre of Chemistry, University of Minho, Campus de Gualtar, 4710-057 Braga, Portugal; [email protected] (C.A.); [email protected] (T.P.); [email protected] (J.A.M.); [email protected] (P.M.T.F.) * Correspondence: [email protected] Abstract: Supramolecular peptide hydrogels are gaining increased attention, owing to their potential in a variety of biomedical applications. Their physical properties are similar to those of the extracel- lular matrix (ECM), which is key to their applications in the cell culture of specialized cells, tissue engineering, skin regeneration, and wound healing. The structure of these hydrogels usually consists of a di- or tripeptide capped on the N-terminus with a hydrophobic aromatic group, such as Fmoc or naphthalene. Although these peptide conjugates can offer advantages over other types of gelators such as cross-linked polymers, they usually possess the limitation of being particularly sensitive to proteolysis by endogenous proteases. One of the strategies reported that can overcome this barrier is to use a peptidomimetic strategy, in which natural amino acids are switched for non-proteinogenic analogues, such as D-amino acids, β-amino acids, or dehydroamino acids. Such peptides usually possess much greater resistance to enzymatic hydrolysis. Peptides containing dehydroamino acids, Citation: Jervis, P.J.; Amorim, C.; i.e., dehydropeptides, are particularly interesting, as the presence of the double bond also intro- Pereira, T.; Martins, J.A.; Ferreira, duces a conformational restraint to the peptide backbone, resulting in (often predictable) changes P.M.T.
    [Show full text]
  • Highly Stereoselective and Efficient Synthesis of the Dopa Analogue In
    Turk J Chem 34 (2010) , 181 – 186. c TUB¨ ITAK˙ doi:10.3906/kim-0904-14 Highly stereoselective and efficient synthesis of the dopa analogue in pepticinnamin E via enantioselective hydrogenation of dehydroamino acids Dequn SUN Marine College, Shandong University at Weihai, Weihai 264209, P. R. CHINA e-mail: [email protected] Received 13.04.2009 An efficient and new method was developed to prepare the dopa analogue 11 in natural pepticinnamin via catalytic hydrogenation of dehydroamino acids (DDAA) with a good yield and ee. Product 11 is a key intermediate towards the total synthesis of pepticinnamin E and its analogues. Key Words: Synthesis; dopa analogue; enantioselective hydrogenation; dehydroamino acid. Introduction Pepticinnamin E1 (Figure) is a major product of the pepticinnamins, which are isolated from the culture of Streptomyces sp. OH-4652. It was identified as a depsipeptide having an O − Z -pentenylcinnamin acid and a novel dopa analogue, whose configuration has been determined as S by the Waldmann group using the Sch¨ollkopf method. 2 Pepticinnamin E shows rather potent inhibitory activity against farnesyl protein transferase (FPTase) with an IC 50 of 0.3 μM and is the first competitive inhibitor derived from a natural product. Our interest in the exploitation of a new methodology to synthesise naturally bioactive peptides containing non-ribosomal amino acids led us to initiate the synthesis of pepticinnamin E (1). Emphasis was placed on preparing both dopa analogue 2 and O − Z -pentenylcinnamin acid. 3 This study reports the enantioselective synthesis of the precursor of the dopa analogue 2, which would be suitable for the total synthesis of pepticinnamin E and its analogues.
    [Show full text]
  • Phosphorus-Containing Amino Acids with a P–C Bond in the Side Chain Or a P–O, P–Sorp–N Bond: Cite This: RSC Adv., 2020, 10, 6678 from Synthesis to Applications
    RSC Advances View Article Online REVIEW View Journal | View Issue Phosphorus-containing amino acids with a P–C bond in the side chain or a P–O, P–SorP–N bond: Cite this: RSC Adv., 2020, 10, 6678 from synthesis to applications a b b Mathieu Arribat, Florine Cavelier * and Emmanuelle Remond´ * Since the discovery of (L)-phosphinothricin in the year 1970, the development of a-amino acids bearing a phosphorus group has been of renewed interest due to their diverse applications, including their use in [18F]-fluorolabeling, as fluorescent probes, as protecting groups and in the reversible immobilization of amino acids or peptide derivatives on carbon nanomaterials. Considerable progress has also been achieved in the field of antiviral agents, through the development of phosphoramidate prodrugs, which increase significantly the intracellular delivery of nucleoside monophosphate and monophosphonate analogues. This review aims to summarize the strategies reported in the literature for the synthesis of P(III), P(IV) and P(V) phosphorus-containing amino acids with P–C, P–O, P–SorP–N bonds in the side Received 2nd December 2019 Creative Commons Attribution-NonCommercial 3.0 Unported Licence. chains and their related applications, including their use in natural products, ligands for asymmetric Accepted 22nd January 2020 catalysis, peptidomimetics, therapeutic agents, chemical reagents, markers and nanomaterials. The DOI: 10.1039/c9ra10917j discussion is organized according to the position of the phosphorus atom linkage to the amino acid side rsc.li/rsc-advances chain, either in an a-, b-, g-ord-position or to a hydroxyl, thiol or amino group. 1. Introduction phosphinothricin has engendered the development of numerous drugs for neurodegenerative disease treatment.
    [Show full text]
  • Sandra Cristina Gomes Oliveira Aminoácidos Não-Proteinogénicos
    Universidade do Minho Escola de Ciências Sandra Cristina Gomes Oliveira Aminoácidos não-proteinogénicos como antioxidantes Aminoácidos não-proteinogénicos como antioxidantes Aminoácidos não-proteinogénicos como antioxidantes Sandra Cristina Gomes Oliveira Cristina Gomes Oliveira Sandra Minho | 2016 U Outubro de 2016 Universidade do Minho Escola de Ciências Sandra Cristina Gomes Oliveira Aminoácidos não-proteinogénicos como antioxidantes Tese de Mestrado Mestrado em Química Medicinal Trabalho efetuado sob a orientação de Doutor Luís Miguel Oliveira Sieuve Monteiro e de Doutora Maria de Fátima Azevedo Brandão Amaral Paiva Martins Outubro de 2016 Agradecimentos O projeto que desenvolvi ao longo do segundo ano de mestrado, só foi possível graças à colaboração de diversas pessoas que, ajudaram na sua realização, às quais aproveito desde já para agradecer. Em primeiro lugar, gostaria de agradecer ao Doutor Luís Monteiro e à Doutora Paula Ferreira, pelo enorme e incansável apoio, pelos seus ensinamentos, paciência e disponibilidade. À Doutora Fátima Paiva-Martins da Faculdade de Ciências da Universidade do Porto, agradeço por me ter proporcionado a oportunidade de desenvolver uma parte deste trabalho na Faculdade de Ciências da Universidade do Porto, pela sua orientação, ensinamento, disponibilidade e apoio. Gostaria também de agradecer aos meus amigos de mestrado pelo companheirismo e os momentos agradáveis. Aos meus colegas que estiveram comigo no laboratório da Faculdade de Ciências da Universidade do Porto por toda a ajuda que deram a integrar- me no laboratório nos primeiros tempos de trabalho. Agradeço também aos restantes amigos. Quero agradecer de uma forma muito especial à minha família que sempre se mostrou presente, disponível e compreensiva, principalmente aos meus pais por fazerem de mim aquilo que sou hoje.
    [Show full text]
  • Copyrighted Material
    353 Index a aromatic 1,2-diphosphines 84 absolute asymmetric synthesis 67, 88 aspergillomarasmine 10 acetaldehyde 48, 203, 223, 292, 321 asymmetric synthesis (ÀS) acetic acid moiety 207, 321 – absolute asymmetric synthesis 67 acetic anhydride 51, 93, 209 – classification 51, 67 acetoacetic ether 129 – diastereoselective asymmetric synthesis 67 acetonitrile 51, 100, 103, 227, 236, 360 –effectivenessof 67 acetoxy-ion elimination 58 – enantiomeric asymmetric synthesis 68 (R)-O-acetylserine complex 294 – partial asymmetric synthesis 67 (S)-O-acetylserine complex 204, 293 atropoisomer 296 acrylic acid 113, 120 azetidine-2-carboxylic acid 8 alanine alkylation 215, 220 alanopine 4, 7, 11 aldol condensation 111, 188, 222, 223 b aldol reaction 159, 224 Bacillus brevis 2 alkylhalides 115, 152, 216 Balz–Schiemann reaction 264 allyl chloride 218 benzaldehyde 147, 148–151, 162 aluminum nitrate 39 benzophenone moiety 96, 97 amino acid moiety 47, 110, 186 benzylamine 100, 102, 176 -amino aldehydes 173 benzylation reaction 82, 111 2-amino-2’-carboxyindan 95 benzylbromide 82, 111, 140, 143, 145, 184, 2-aminoacetophenone 190, 201, 285 218, 290, 318 2-aminoacrylic acid 99 benzylcinchonidine 75 aminobinaphthols 104, 106, 112, 114, 125 benzylcinchonine 81 3-aminobutanoic acid 179 (S)-2-N-(N’-benzylprolyl)aminobenzophenone -aminobutyric acid (GABA) 2 (BPB) 200 1-aminocyclopropanecarboxylic acid (ACC) (S)-BINOLAM 81 85 biomimetic chemical approach 25 1-amino-2,2-dideuterocyclopropanecarboxylicCOPYRIGHTEDbiomimetic enzymeMATERIAL systems 25 acid 85 Δ-bis[N-3-methylsalicylideneglycinate]sodium
    [Show full text]
  • Synthesis of Bis-Dehydroamino Acid Derivatives by Suzuki
    View metadata, citation and similar papers at core.ac.uk brought to you by CORE provided by Universidade do Minho: RepositoriUM High yielding synthesis of N-ethyl dehydroamino acids Luís S. Monteiro* and Ana S. Suárez Chemistry Centre, University of Minho, Gualtar, 4710-057 Braga, Portugal Author’s address: L. S. Monteiro, Chemistry Centre, University of Minho, Gualtar, 4710-057 Braga, Portugal, Fax: +351 253604382, e-mail: [email protected]. Abstract. Recently we reported the use of a sequence of alkylation and dehydration methodologies to obtain N-ethyl-- dehydroamino acid derivatives. The application of this N-alkylation procedure to several methyl esters of -dibromo and - bromo, -substituted dehydroamino acids protected with standard amine protecting groups was subsequently reported. The corresponding N-ethyl, -bromo dehydroamino acid derivatives were obtained in fair to high yields and some were used as substrates in Suzuki cross coupling reactions to give N-ethyl, -disubstituted dehydroalanine derivatives. Herein, we further explore N-ethylation of -halo dehydroamino acid derivatives using triethyloxonium tetrafluoroborate as alkylating agent but substituting N,N-diisopropylethylamine for potassium tert-butoxide as auxiliary base. In these conditions, for all -halo dehydroamino acid derivatives, reactions were complete and the N-ethylated derivative could be isolated in high yield. This method was also applied for N-ethylation of non-halogenated dehydroamino acids. Again, with all compounds the reactions were complete and the N-ethyl dehydroamino acid derivatives could be isolated in high yields. Some of these N-ethyl dehydroamino acid methyl ester derivatives were converted in high yields to their corresponding acids and coupled to an amino acid methyl ester to give N-ethyl dehydrodipeptide derivatives in good yields.
    [Show full text]
  • N,N-Diprotected Dehydroamino Acid Derivatives: Versatile Substrates for the Synthesis of Novel Amino Acids
    N,N-DIPROTECTED DEHYDROAMINO ACID DERIVATIVES: VERSATILE SUBSTRATES FOR THE SYNTHESIS OF NOVEL AMINO ACIDS Paula M. T. Ferreira and Luís S. Monteiro Department of Chemistry, University of Minho, Gualtar, 4710-057 Braga, Portugal (e-mail: [email protected]) Abstract. Non-proteinogenic amino acids are an important class of organic compounds that can have intrinsic biological activity or can be found in peptides with antiviral, antitumor, anti-inflammatory or immunosuppressive activities. This type of compounds is also important in drug development, in the elucidation of biochemical pathways and in conformational studies. Therefore, research towards efficient methods that allow the synthesis of these compounds constitutes an important area of peptide chemistry. In our laboratories we have developed a new and high yielding method for the synthesis of N,N-diprotected dehydroamino acid derivatives using tert-butyl pyrocarbonate and 4-dimethylaminopyridine. These compounds were used as substrates in several types of reactions, allowing the synthesis of a variety of new amino acid derivatives. Some of these new compounds are heterocyclic systems or contain heterocyclic moieties such as pyrazole, indole, or imidazole. Thus, several nitrogen heterocycles were reacted with N,N-diprotected dehydroalanine to give new β-substituted alanines and dehydroalanines. Furanic amino acids were obtained treating the methyl ester of N-(4-toluenesulfonyl), N-(tert-butoxycarbonyl) dehydroalanine with carbon nucleophiles of the β-dicarbonyl type having at least one methyl group attached to one of the carbonyl groups. Treatment of these furanic amino acids with trifluoracetic acid afforded pyrrole derivatives in good to high yields. A N,N-diprotected 1,4-dihydropyrazine was obtained reacting the methyl ester of N-(4-toluenesulfonyl), N-(tert-butoxycarbonyl)dehydroalanine with 4-dimethylaminopyridine and an excess of potassium carbonate.
    [Show full text]
  • 1 the Historical Development of Asymmetric Hydrogenation
    1 1 The Historical Development of Asymmetric Hydrogenation John M. Brown Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK 1.1 Introduction How did chemists gain the current levels of knowledge and expertise for control- ling molecular chirality through hydrogenation or otherwise? The desirability of asymmetric synthesis was recognized in the 1880s by Emil Fischer and others, but practical solutions only arose more than 80 years later. The key reasons are explored here. This brief review has five main Sections 1.2–1.6, covering first the development of ideas underpinning our understanding of asymmetry, then the initial applications to asymmetric synthesis, and also the development of asymmetric heterogeneous hydrogenation of alkenes. The final sections on asymmetric homogeneous hydro- genation of alkenes are limited to work published in or before the early 1980s, in advance of extensive developments, and thus excluding the important inputs of irid- ium catalysts and more recently early transition metals. 1.2 Early Work on the Recognition of Molecular Asymmetry Chemistry was an emerging science by the beginning of the nineteenth century with many opportunities for fundamental discovery. At that time scientists crossed dis- ciplines easily; optics and mineralogy played important roles because of the ready accessibility and verifiable purity of solid substances. Malus had invented the first polarimeter in 1808, enabling measurement of both the sense and magnitude of rota- tion of plane-polarized light [4]. Following this, work by Arago and others on the interaction of polarized light with minerals intensified in the following decade [5]. Haüy had earlier concluded that each type of crystal has a fundamental primitive, nucleus or “integrant molecule” of a particular shape, that could not be broken fur- ther without destroying both the physical and chemical nature of the crystal.
    [Show full text]
  • (2H, 13C, 15N, 17O and 18O) in Genetically Encoded Amino Acids
    Molecules 2013, 18, 482-519; doi:10.3390/molecules18010482 OPEN ACCESS molecules ISSN 1420-3049 www.mdpi.com/journal/molecules Review Access to Any Site Directed Stable Isotope (2H, 13C, 15N, 17O and 18O) in Genetically Encoded Amino Acids Prativa B. S. Dawadi and Johan Lugtenburg * Leiden Institute of Chemistry, Leiden University, P.O. Box 9502, 2300 RA, Leiden, The Netherlands; E-Mail: [email protected] * Author to whom correspondence should be addressed; E-Mail: [email protected]. Received: 25 October 2012; in revised form: 10 December 2012 / Accepted: 24 December 2012 / Published: 2 January 2013 Abstract: Proteins and peptides play a preeminent role in the processes of living cells. The only way to study structure-function relationships of a protein at the atomic level without any perturbation is by using non-invasive isotope sensitive techniques with site-directed stable isotope incorporation at a predetermined amino acid residue in the protein chain. The method can be extended to study the protein chain tagged with stable isotope enriched amino acid residues at any position or combinations of positions in the system. In order to access these studies synthetic methods to prepare any possible isotopologue and isotopomer of the 22 genetically encoded amino acids have to be available. In this paper the synthetic schemes and the stable isotope enriched building blocks that are available via commercially available stable isotope enriched starting materials are described. Keywords: amino acids; isotope labelling; [5-13C]-leucine; [4-13C]-valine; 13C or 15N-enriched L-lysine; [18O]-benzylchloromethyl ether; [13C]-benzonitrile 1. Introduction Proteins and peptides play a preeminent role in living cells, such as receptor action, enzyme catalysis, transport and storage, hormone action, mechanical support, immune protection, etc.
    [Show full text]
  • 353 Absolute Asymmetric Synthesis 67, 88
    353 Index a aromatic 1,2-diphosphines 84 absolute asymmetric synthesis 67, 88 aspergillomarasmine 10 acetaldehyde 48, 203, 223, 292, 321 asymmetric synthesis (ÀS) acetic acid moiety 207, 321 – absolute asymmetric synthesis 67 acetic anhydride 51, 93, 209 – classification 51, 67 acetoacetic ether 129 – diastereoselective asymmetric synthesis 67 acetonitrile 51, 100, 103, 227, 236, 360 –effectivenessof 67 acetoxy-ion elimination 58 – enantiomeric asymmetric synthesis 68 (R)-O-acetylserine complex 294 – partial asymmetric synthesis 67 (S)-O-acetylserine complex 204, 293 atropoisomer 296 acrylic acid 113, 120 azetidine-2-carboxylic acid 8 alanine alkylation 215, 220 alanopine 4, 7, 11 aldol condensation 111, 188, 222, 223 b aldol reaction 159, 224 Bacillus brevis 2 alkylhalides 115, 152, 216 Balz–Schiemann reaction 264 allyl chloride 218 benzaldehyde 147, 148–151, 162 aluminum nitrate 39 benzophenone moiety 96, 97 amino acid moiety 47, 110, 186 benzylamine 100, 102, 176 -amino aldehydes 173 benzylation reaction 82, 111 2-amino-2’-carboxyindan 95 benzylbromide 82, 111, 140, 143, 145, 184, 2-aminoacetophenone 190, 201, 285 218, 290, 318 2-aminoacrylic acid 99 benzylcinchonidine 75 aminobinaphthols 104, 106, 112, 114, 125 benzylcinchonine 81 3-aminobutanoic acid 179 (S)-2-N-(N’-benzylprolyl)aminobenzophenone -aminobutyric acid (GABA) 2 (BPB) 200 1-aminocyclopropanecarboxylic acid (ACC) (S)-BINOLAM 81 85 biomimetic chemical approach 25 1-amino-2,2-dideuterocyclopropanecarboxylic biomimetic enzyme systems 25 acid 85 Δ-bis[N-3-methylsalicylideneglycinate]sodium 4-aminoglutamic acid 240, 289 cobaltate (III) 40 6-aminohexanoic acid (-aminocaproic acid) Λ-bis-[N-3-methylsalicylidene-(S)-threoninate]sodium 2 cobaltate (III) 45 -aminopropionitrile 8 bis-[N-7-methylsalicylidene-(S)-threonine]sodium -aminosulfone 188 cobaltate (III) complex 47 anthranilic acid 92, 287 bis-[N-salicylideneaminoacetate]sodium apoenzyme function 30 cobaltate (III) 43 arenechromiumtricarbonyl complexes 265 bisalkylation product 96 Asymmetric Synthesis of Non-Proteinogenic Amino Acids, First Edition.
    [Show full text]
  • Benzophenone Schiff Bases of Glycine Derivatives: Versatile Starting Materials for the Synthesis of Amino Acids and Their Derivatives
    ACCEPTED MANUSCRIPT ODonnell Benzophenone Schiff Bases MS Ghosez Revd 031419.doc Benzophenone Schiff Bases of Glycine Derivatives: Versatile Starting Materials for the Synthesis of Amino Acids and Their Derivatives Martin J. O’Donnell Department of Chemistry and Chemical Biology, Indiana University Purdue University Indianapolis, Indianapolis, IN 46250 USA Abstract This review focuses on the introduction and early development, in solution, of phase-transfer catalyzed (PTC) reactions to afford racemic or enantioenriched natural and unnatural amino acids. To form monosubstituted amino acids alkylation reactions are performed on the benzophenone Schiff base of glycine. For α,α-disubstituted amino acids the activated intermediate is an aldimine derivative of the monosubstituted amino acid. Enantioenriched products are produced by organocatalysis using derivatives of Cinchona alkaloids as the phase- transfer catalyst. Selectivity for monoalkylatation and lack of product racemization depend on the acidities of the glycine imines, and dialkylated products are formed from aldimine esters of monoalkyl amino acids. The racemic and catalytic enantioselective reactions of a cationic glycine equivalent with organoboranes, organometallics and malonate anion are discussed as are other reactions of these versatile Schiff bases derivatives. Keywords Amino Acid Synthesis Unnatural Amino Acids Phase-Transfer Catalysis (PTC) MANUSCRIPT Asymmetric Synthesis Benzophenone Schiff Bases Imines of Amino Acid Derivatives Organocatalysis Racemic and Stereoselective Reactions Glycine and Other Amino Acid Anion Equivalents Glycine Cation Equivalents Contents 1. Introduction 3 2. Protected glycine equivalents for amino acid synthesis 1903-1985 4 3. Preparation of Schiff bases of amino acid and dipeptide esters 5 4. Phase-transfer alkylations of the Schiff base esters of glycine and aminoacetonitrile 7 5.
    [Show full text]
  • Organic & Biomolecular Chemistry
    Organic & Biomolecular Chemistry Accepted Manuscript This is an Accepted Manuscript, which has been through the Royal Society of Chemistry peer review process and has been accepted for publication. Accepted Manuscripts are published online shortly after acceptance, before technical editing, formatting and proof reading. Using this free service, authors can make their results available to the community, in citable form, before we publish the edited article. We will replace this Accepted Manuscript with the edited and formatted Advance Article as soon as it is available. You can find more information about Accepted Manuscripts in the Information for Authors. Please note that technical editing may introduce minor changes to the text and/or graphics, which may alter content. The journal’s standard Terms & Conditions and the Ethical guidelines still apply. In no event shall the Royal Society of Chemistry be held responsible for any errors or omissions in this Accepted Manuscript or any consequences arising from the use of any information it contains. www.rsc.org/obc Page 1 of 11 OrganicPlease & Biomoleculardo not adjust margins Chemistry Journal Name REVIEW Synthesis and Bioactivity of Antitubercular Peptides and Peptidomimetics: an Update Received 00th January 20xx, a a a,b Accepted 00th January 20xx Luis M. De Leon Rodriguez,* Harveen Kaur and Margaret A. Brimble* Manuscript DOI: 10.1039/x0xx00000x Mycobacterium tuberculosis is the causative agent of tuberculosis (TB), an infection that has been declared a global public health emergency by the World Health Organization. Current anti-TB therapies are limited in their efficacy and have failed www.rsc.org/ to prevent the spread of TB, due to the long term drug compliance required and the genesis of multidrug-resistant strains (MDR).
    [Show full text]